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Pharm Biol, Early Online: 1–5
! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/13880209.2015.1025288

ORIGINAL ARTICLE

Ellagic acid enhances the antinociceptive action of carbamazepine in

the acetic acid writhing test with mice
Bahareh Naghizadeh1, Mohammad Taghi Mansouri2, and Behnam Ghorbanzadeh3
1
Department of Pharmacology, Medical School, Pain and Physiology Research Centers, Ahvaz Jundishapur University of Medical Sciences, Ahvaz,
Iran, 2Department of Pharmacology, Medical School, Physiology and Atherosclerosis Research Centers, Ahvaz Jundishapur University of Medical
Sciences, Ahvaz, Iran, and 3Department of Pharmacology, Medical School, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Abstract Keywords
Context: Ellagic acid (EA) produced antinociceptive and anti-inflammatory effects through the Analgesia, isobolographic analysis, visceral
central and peripheral sites of action. pain
Objective: The objective of the current study was to examine the functional interaction between
ellagic acid and carbamazepine (CBZ) on pain. History
Materials and methods: Fourteen groups of mice (8–10 each) were used in this study. Pain was
induced by intraperitoneal acetic acid in mice (writhing test) and the functional interaction Received 21 August 2014
was analyzed using the isobolographic method. EA at doses 0.3, 1, 3, and 10 mg/kg and Revised 19 February 2015
carbamazepine at doses 3, 10, 20, and 30 mg/kg, alone and also in combination (1/2, 1/4, and Accepted 26 February 2015
1/8 of the drug’s ED50) were intraperitoneally administered 30 min before acetic acid (0.6% v/v). Published online 21 April 2015
Then, the abdominal writhes were counted during a 25-min period.
For personal use only.

Results: EA (0.3–10 mg/kg, i.p.) and CBZ (3–30 mg/kg, i.p.) inhibited the writhing response
evoked by acetic acid. Fifty percent effective dose (ED50) values against this tonic pain were
1.02 mg/kg and 6.40 mg/kg for EA and CBZ, respectively. The antinociception induced by EA
showed higher potency than that of carbamazepine. Co-administration of increasing fractional
increments of ED50 values of EA and CBZ produced additive interaction against writhing
responses, as revealed by isobolographic analysis.
Discussion and conclusion: These results suggest that a combination of carbamazepine and
ellagic acid may be a new strategy for the management of neuropathic pain such as what
occurs in trigeminal neuralgia, since the use of carbamazepine is often limited by its adverse
effects and by reduction of its analgesic effect through microsomal enzyme induction.

Introduction eucalyptus species, and nuts. This bioflavonoid compound

has been reported to have antioxidant, antifibrotic, cardio-
The development of new pain strategy involves combining
protective, anticancer (Girish & Pradhan, 2008), neuropro-
analgesic drugs to receive greater analgesia at reduced doses
tective (Dolatshahi et al., 2015; Girish et al., 2012), anti-
of individual drugs and lower side effects, both of which are
inflammatory, and antinociceptive properties (Gainok et al.,
very important in improving patient health (Tallarida, 2001).
2011). It has been found to have antidepressant-like activity
Plant polyphenols are bioactive compounds which possess
and its effect is dependent on the interaction with the central
multiple neuroprotective actions in some central nervous
serotonergic (5-HT1, 5-HT2, and 5-HT3 receptors) and
pathophysiological conditions, especially the pain regulation
noradrenergic (a1 and a2 adrenoceptors) systems (Girish
(Ullah & Khan, 2008).
et al., 2012). Also, Girish et al. (2013) proved the involvement
Ellagic acid (EA) (2,3,7,8-tetrahydroxy-[1]-benzopyranol-
of the GABAergic system in the anxiolytic-like effect of EA.
[5,4,3-cde]-[1]-benzopyran-5,10-dione) is a polyphenolic
Recently, we have shown the central and peripheral
agent that occurs largely as ellagitannins in plants such as
antinociceptive activities of EA which were mediated by
pomegranate juice, raspberries, the stem and bark of
opioid and L-arginine/NO/cGMP/ATP-sensitive K+ channel
pathways in different experimental models of pain (Mansouri
et al., 2013, 2014).
Antiepileptic drugs such as oxcarbazepine, gabapentin, and
Correspondence: Mohammad Taghi Mansouri, Department of topiramate are likely to produce analgesia. In addition, these
Pharmacology, Medical School, Physiology and Atherosclerosis drugs have been reported to show antinociceptive or
Research Centers, Ahvaz Jundishapur University of Medical Sciences, antihyperalgesic effects in animal models of neuropathic,
Golestan Blvd, P.O. Box 61355-45, Ahvaz, Iran. Tel: +98 611 3330074.
Fax: +98 611 3332036. E-mail: mansouri_smt@yahoo.com, mansouri- inflammatory somatic, and visceral pain (Stepanovic-Petrovic
m@ajums.ac.ir et al., 2008). Carbamazepine is one of the therapeutic choices
 2 B. Naghizadeh et al. Pharm Biol, Early Online: 1–5

that has been used as an analgesic to treat neuropathic pain, vehicles were given 30 min before acetic acid.
especially pain caused by trigeminal neuralgia. However, the Antinociceptive activity (reduction in writhes) was expressed
use of carbamazepine is often limited by its side effects such as percent maximum possible effect (%MPE) that was
as dizziness, somnolence, gait, and hematological abnormal- calculated by the following equation: %MPE ¼ [100  (mean
ities (Backonja, 2002; Jensen, 2002). Furthermore, the writhes in control group-mean writhes in drug(s) treated
chronic use of carbamazepine reduces its analgesic effect group)]/mean of writhes in control group (Jain et al., 2001).
due to liver microsomal enzyme induction (Benedetti et al., Eight to ten animals were used at each of the dose levels to
2005). It has been reported that the antinociceptive effect determine the ED50 value for a drug. The antinociceptive
of carbamazepine is potentiated when combined with anti- effects of EA (0.3, 1, 3, and 10 mg/kg) and CBZ (3, 10, 20,
depressants such as fluvoxamine, imipramine, or milnacipran and 30 mg/kg) administered either alone or in combination
(Aoki et al., 2006). were studied.
Considering the studies mentioned above, the present study
was designed to elucidate the interaction of EA with the Isobolographic analysis
analgesic activity of carbamazepine using isobolographic
A graphical assessment of synergy was carried out using
analysis in the mouse acetic acid-induced writhing test.
isobolographic analysis. In the present study, the interaction
of antinociceptive effect of EA with CBZ was evaluated by
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Materials and methods

simultaneous administration of fixed proportions of EA with
Animals CBZ, as described by Tallarida et al. (1997). The isobologram
was constructed by connecting the ED50 value (dose that
Adult male Swiss albino mice weighing between 25 and 30 g
produced 50% of antinociception) of CBZ, plotted on the
were obtained from the animal house of Ahvaz Jundishapur
ordinate with the ED50 value of EA plotted on the abscissa to
University of Medical Sciences (Iran). The animals were
obtain the additive line. For drug combination, ED50 value
housed at controlled temperature (22 ± 2  C) and allowed free
and an associated 95% confidence interval (CIs) were
access to food and drinking water. Testing took place in the
determined by linear regression analysis of the log dose–
middle of the light period of a 12 h light/dark cycle. All
response data and the equation of the straight line. For
animal experiments were carried out in accordance with the
interaction studies, fixed-ratio proportions were selected by
NIH Guide for Care and Use of Laboratory Animals. The
first combining the ED50 value of each compound and then
For personal use only.

Institutional Animal Ethical Committee of Jundishapur

constructing a dose–response curve in which ED50 fractions
University, formed under Committee for Purpose of Control
(1/2, 1/4, and 1/8) of drug combinations were administered
and Supervision of Experiments on Animals (CPCSEA, Reg.
(Miranda & Pinardi, 2004; Pinardi et al., 2005). The variance
no. PRC115) approved the pharmacological protocols. All
of ED50(add) value was calculated from the fraction of the
behavioral observations were carried out as blinded studies.
ED50 value (i.e., 0.5) in the combination as Var ED50(add) ¼
0.52  Var ED50 EA + 0.52  Var ED50 CBZ. From these
Drugs and chemicals
variances, 95% confidence intervals were calculated and
Acetic acid was purchased from Merck Co (Darmstadt, resolved according to the ratio of the individual drugs in the
Germany) and dissolved in physiologic saline solution (0.9% combination. Supra-additivity or synergistic effect is defined
sodium chloride). Ellagic acid hydrochloride (Sigma-Aldrich, as the effect of a drug combination that is higher and
St. Louis, MO) and carbamazepine (Jalinous Pharmaceutical statistically different (ED50 significantly lower) than the
Co., Tehran, Iran) were dissolved in the physiologic saline theoretical calculated equi-effect of a drug combination with
solution containing 10% and 40% DMSO, respectively. Drug the same proportions. When the drug combination gives an
concentrations were freshly prepared in such a way that the experimental ED50 value not statistically different from the
necessary dose could be injected intraperitoneally in a volume theoretically calculated ED50 value, the combination has an
of 5 ml/kg. Doses and drug administration schedules were additive effect and additivity means that each constituent
selected based on the previous reports (Beltz et al., 2008; contributes with its own potency and the less potent drug is
Rogerio et al., 2006) and our experiments in lab (Mansouri acting as though it is merely a diluted form of the other
et al., 2013). (Miranda & Pinardi, 2004; Pinardi et al., 2005; Tallarida
et al., 1997).
Measurement of analgesic activity
Statistical analysis
The writhing test was selected as a model of acute visceral
pain, because it can be a model of clinical relevant intestinal Results are presented as mean values ± SEM or as ED50
pain in humans (Reichter et al., 2001). All animals were values and 95% CIs. The antinociceptive effects of EA and
acclimatized to laboratory environment for at least 2 h before CBZ were examined by one-way analysis of variance
testing. Mice were injected i.p. with 10 ml/kg of 0.6% acetic (ANOVA) followed by Tukey’s post hoc test. Unpaired
acid according to the method described previously Student’s t-test was used to compare the experimental and
(Mansouri et al., 2013). The number of abdominal writhes theoretical ED50 value to determine the mechanisms of the
was counted during a 25-min period, starting 5 min after the interaction between EA and CBZ. The difference was
administration of acetic acid solution. A writhe was defined considered significant at 5% level. All data calculations and
as a contraction of the abdominal muscles following by statistical analysis were done by using the GraphPad Prism
body elongation and hind limbs’ extension. Drugs and their Version 5.01 (GraphPad Software Inc., San Diego, CA).
 DOI: 10.3109/13880209.2015.1025288 Interaction between ellagic acid and carbamazepine in pain 3

Figure 2. Dose–response curves for the antinociception induced by

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ellagic acid (EA; i.p.), carbamazepine (CBZ; i.p.) alone and in

combination in the mouse acetic acid-induced writhing test. Data are
the mean ± SEM of 10–12 animals per group.
For personal use only.

Figure 1. Effects of intraperitoneal (A) ellagic acid (EA; 0.3–10 mg/kg)

or (B) carbamazepine (CBZ; 3–30 mg/kg) in the mouse acetic acid-
induced writhing test. Data are the mean ± SEM of 8–10 animals
per group (one-way ANOVA followed by Tukey’s test). **p50.01,
***p50.001 versus the vehicle (VEH) control group.

Results
Figure 3. Isobologram for the co-administration of ellagic acid (EA, i.p.)
Antinociceptive effects of EA and carbamazepine and carbamazepine (CBZ; i.p.) on acetic acid-induced writhing in mice.
Horizontal lines in the abscissa and the ordinate represent the S.E.M. of
Results showed that the intraperitoneal administration of
the corresponding ED50. Filled circles correspond to the theoretical and
ellagic acid (EA) and carbamazepine (CBZ) produced dose- experimental ED50 values with 95% confidence intervals.
dependent antinociception (Figure 1A and B, respectively).
The value of ED50 with 95% confidence intervals (CIs) for EA
was lower than the ED50 value for carbamazepine indicating EA with CBZ revealed that the experimental ED50 was 2.94
greater potency in antinociceptive effect of ellagic acid in the (1.14–4.74) mg/kg. This experimental ED50 value was below
test [ED50 values were 1.02 (0.86–1.19) and 6.40 (5.47–7.32) the additive line, and also statistical analysis demonstrated
mg/kg for EA and CBZ, respectively]. Animals treated that it was not significantly different from its correspond-
with ellagic acid did not show any significant behavioral or ing theoretical ED50 value (p40.05). Therefore, EA and CBZ
motor dysfunctions in locomotor activity assessment (data interacted in an additive fashion in the writhing test
not shown). (Figure 3).

Analysis of interaction Discussion

The antinociceptive activity induced by the co-administration An effective control of pain is difficult to attain when using
of fixed ratios of ED50 fractions for EA and CBZ was one drug alone. So, the development of new pain relief
examined by isobolographic analysis. Figure 2 shows a log strategies involves multiple combinations of analgesics that
dose–response curve obtained for EA, CBZ, and their point both central and peripheral nociceptive pathways to
combination administered. The theoretical ED50 values for produce greater analgesia at reduced and more tolerable doses
the combination and their 95% confidence intervals were of individual drugs (Kehlet & Dahl, 1993; Mehlisch, 2002;
calculated at 3.71 (3.27–4.15) mg/kg. Co-administration of Tallarida, 2001). A combination of small-dose carbamazepine
 4 B. Naghizadeh et al. Pharm Biol, Early Online: 1–5

with other analgesics could result in analgesia without the antinociceptive effects of this drug in the visceral pain model,
adverse effect associated with large-dose used. In the present it may suggest that the inflammatory nature of nociception in
study, carbamazepine and ellagic acid alone exhibited com- writhing and paw pressure tests leading to a facilitated state
parable dose-dependent antinociceptive activity in the acetic may be similar. It has been shown that activation of central
acid-induced writhing test. Also, co-administration of a adenosine A1 (Stepanovic-Petrovic et al., 2008) and adren-
carbamazepine with ellagic acid resulted in an additive ergic a2 (Vucvkovic et al., 2006) receptors and also inhibition
antinociceptive interaction. of tetrodotoxin-resistant sodium channels in dorsal root
Previous studies suggested that the CNS depression and ganglion neurons (Brau et al., 2001) produced antinociception
the non-specific muscle relaxation effect can reduce the in the writhing test. Therefore, it could be suggested that the
response of motor coordination and might invalidate the peripheral and/or central component of nociceptive pathways
nociceptive test results (Santos et al., 2005). Ellagic acid has was involved in the antinociception produced by carbamaze-
little or no effect on motor function even at a dose as high as pine in writhing test.
30 mg/kg, when tested with both the open-field and also rota- In the present study, an isobolographic analysis revealed
rod tests (Mansouri et al., 2013, 2014). Therefore, the present additive interaction between carbamazepine and ellagic acid.
result indicates that ellagic acid may have antinociceptive There is no scientific evidence available to support the results
activity in mice. obtained in this work; however, such interaction has not been
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In this study, we used the acetic acid writhing test as an studied previously in a valuable experiment. It should be
inflammatory pain model stimulus for acute nociception. In noticed that an additive interaction might be exhibited if
this test, acetic acid causes tissue damage and releases pain- fundamentally the activation of common mechanisms is
producing substances, including prostaglandins, which acti- simultaneously engaged in the antinociception of a combin-
vate peripheral nociceptors on the terminals of sensory nerve ation (Solomon & Gebhart, 1994). Therefore, ellagic acid and
fibers. Painful stimuli caused by acetic acid reach higher carbamazepine may act through a common pathway.
centers by a number of spinal nerve pathways. Thus, this Our study did not investigate the mechanisms involved in
nociceptive test is used for determining both central and the nature of interaction between ellagic acid and carbamaze-
peripheral analgesia (Le Bars et al., 2001; Satyanarayana pine. The observed addition may be related to a pharmaco-
et al., 2004). kinetic or pharmacodynamics interaction.
Flavonoids are shown to have neuroprotective, anxiolytic, Although synergism is optimal, to be clinically useful, a
For personal use only.

sedative, and anticonvulsant activities. The neuroprotective combination of drugs need not necessarily be synergistic but
effects of flavonoids, including ellagic acid, may be mediated needs only to allow exhibition of an increased desired clinical
through direct actions on enzymes, receptors, and signaling result with the same or a lower level of side effects compared
pathways (Spencer, 2009). with a single agent. Therefore, the results observed here may
A growing pieces of evidence indicated that ellagic acid is provide a theoretical basis for the development of a multi-
effective for altering acute visceral pain (Mansouri et al., targeted drug strategy to augment antinociception while
2013; Rogerio et al., 2006). Ellagic acid-induced antinocicep- preventing or reducing the untoward side effects of each
tion in the writhing test is also consistent with the ability of individual drug, thus enhancing analgesic efficacy. Further
this compound to reduce inflammation-induced nociception studies are needed to elucidate the detailed mechanisms of the
caused by a variety of inflammatory agents, such as potentiating effect of the combination of ellagic acid and
carrageenan and formalin (Gainok et al., 2011; Mansouri carbamazepine on the antinociceptive effect in mice, includ-
et al., 2014). The analgesic action of ellagic acid has been ing studies on the pharmacokinetic interactions between
explained by the inhibition of cyclooxygenase, which synthe- carbamazepine and ellagic acid.
sizes prostaglandins at the peripheral cell-damage sites
(El-Shitany et al., 2014; Rogerio et al., 2006). Moreover,
Conclusion
Beltz et al. (2008) demonstrated the antinociceptive effects of
EA in the hot-plate test. In our previous studies, we have In conclusion, isobolographic analysis indicated an additive
shown the central and peripheral antinociceptive effects of EA antinociceptive interaction between ellagic acid and carba-
which were mediated by opioid receptors and L-arginine/NO/ mazepine when administered systemically in an inflammatory
cGMP/ATP-sensitive K+ channel pathway using tail-flick, visceral pain model. Therefore, these findings suggest that co-
formalin, and writhing tests (Ghorbanzadeh et al., 2014; administration of ellagic acid with carbamazepine may be a
Mansouri et al., 2013, 2014). Further studies are needed to new strategy for managing neuropathic pain such as pain
elucidate the mechanism of the antinociceptive action of caused by trigeminal neuralgia, although further investiga-
ellagic acid. tions are necessary to elucidate this combination effect using
Carbamazepine is a well-known anticonvulsant drug which other methods evaluating antinociceptive actions.
is used for the management of bipolar affective disorders, as
well as trigeminal and glossopharyngeal neuralgias
Declaration of interest
(Stepanovic-Petrovic et al., 2008). Carbamazepine-induced
antinociception in the writhing test is consistent with the The authors report that they have no conflicts of interest. This
ability of this drug, in a paw pressure test, to reduce somatic research was financially supported by grants (PRC-115) from
nociception caused by proinflammatory agents (Bianchi et al., the Physiology Research Center, funded by the Vice
1995; Kawaura et al., 2011; Stepanovic-Petrovic et al., 2008). Chancellor of Research, Ahvaz Jundishapur University of
Although our results do not clarify the mechanism of the Medical Sciences (Iran).
 DOI: 10.3109/13880209.2015.1025288 Interaction between ellagic acid and carbamazepine in pain 5

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